There are many applications of materials where retention of a thin film of aqueous fluid is desirable. For example, the retention of an aqueous fluid layer is beneficial for lubrication of catheters, the retention of an aqueous fluid layer can reduce protein fouling on the surface of pacemakers and artificial vascular grafts, or the retention of an aqueous fluid layer can prevent the colonization of a surface by bacteria as they are unable to attach properly. In another aspect, the facile movement of an eyelid over a contact lens is important for the comfort of the wearer; this sliding motion is facilitated by the presence of a continuous layer of tear fluid on the contact lens, a layer which lubricates the tissue/lens interface. However, clinical tests have shown that currently available contact lenses partially dry out between blinks, thus increasing friction between the eyelid and the lens. The increased friction results in soreness of the eyes and movement of the contact lens. Since the average period between blinks is ca. 12 seconds, it would be advantageous to fabricate a wettable and biocompatible contact lens that can hold a continuous layer of tear fluid for more than 12 seconds. Current biomedical materials do not reach this target; for instance, contact lenses fabricated from highly water swellable polymer pHEMA retain such a tear layer for approximately 5 seconds only.
Thus materials with wettable and biocompatible surfaces are highly desirable for many applications. The wettability of materials is strongly dependent on the chemical composition of the material surface. In particular, the ability of the surface to hold a continuous layer of an aqueous solution, such as tear fluid, is affected by the composition of the material surface. Early attempts to solve the wettability problem in the ophthalmic field were based on producing hydrophilic materials. For example, in an attempt to make wettable soft contact lenses, silicone elastomers with pendant epoxy groups were prepared by crosslinking epoxidized silicone compounds (French patent FR 2,622,201, J. M. Frances and G. Wajs). The elastomers were rendered wettable by grafting glucuronic acid onto the epoxy groups. The disadvantage of incorporating hydrophilic species into polymers by bulk synthesis is that the optimum balance of optical properties (e.g., transparency and refractive index), mechanical properties (e.g. strength, hardness, gas permeability and elasticity) and processability of the material obtainable will be worse than conventional materials and may not satisfy the application. The incorporation of hydrophilic monomers is not appropriate for improving the wettability of fluoropolymer- or acrylate-based lenses.
In an attempt to fabricate hard contact lenses which are compatible with the cornea and ocular fluid, dextran ester monovinyl compounds have been copolymerised with various acrylates (Japanese patent JP 63/309914, H. Kitaguni et al.). Dextran/methyl methacrylate copolymers have been prepared by graft polymerisation and have yielded wettable contact lenses (Y. Onishi et al. in Contemp. Top. Polym. Sci. 4, 149 (1984)). The preparation of dextran ester copolymers by bulk polymerisation methods offers limited scope for improving the wettability of contact lenses in general. The disadvantage of incorporating hydrophilic compounds into polymers by bulk synthesis is that the optical properties (e.g., transparency and refractive index), mechanical properties (e.g., strength, hardness, gas permeability and elasticity) and processability of the material cannot be optimized independently.
A method of modifying the surface of contact lenses has been disclosed in GB 2,163,436 (Halpern). According to said method the lens is coated with a carbohydrate which is then crosslinked either covalently with a polyisocyanate or electrostatically with a divalent cation. The process results in a crosslinked skin which is not covalently bonded to the lens and will delaminate when subjected to a shearing force e.g. by an eyelid.
An alternative approach has been disclosed in WO 90/04609 (Sepracor). Polymeric substrates, especially polymeric membranes, having reactive groups such as hydroxy or amino groups at the ends of the polymer chains thereof are reacted with a polyfunctional linker moiety having terminal groups such as epoxy, carbonyl, carboxy, amino, halo, hydroxy, sulfonylhalide, acyl halide, isocyanato, or combinations thereof, which in turn are bonded with a ligand such as hydroxyethylcellulose or dextran. Since the molecular weight of the polymer chains in the substrate is high, the density of chain ends, especially at the surface, will be low, and therefore the density of grafted polysaccharide chains will be low.
The use of dextran and other carbohydrates for surface modification of polymers has also been reported by WO 83/03977, however, in that case the linker moiety is a silane and articles to be treated such as contact lenses are not disclosed.
Additional prior art is directed to modification of the surfaces of contact lenses (U.S. Pat. No. 5,080,924) or ocular implants (WO 93/03776), respectively, wherein amino groups at the surface thereof are reacted with dialdehydes and are then coupled with polysaccharides. However, the reaction of an aldehyde with the hydroxyl groups of a polysaccharide will yield an acid-labile ketal bond.
The above methods all require the presence of the article of a chemically reactive group suitable for the intended covalent reaction. Many materials of interest for ophthalmic applications and implantable biomaterial devices do not possess suitable reactive surface groups, for instance, silicon-based contact lenses and polytetrafluoroethylene vascular grafts. The present invention also comprises methods for the activation of a device surface, the method being generic, so that the surface of any material with suitable bulk properties can be converted to be receptive for the covalent immobilization of a coating which is highly retentious for aqueous layers. In this embodiment of the invention the surface of the polmyeric material is activated preferably by a gas plasma (glow discharge) surface treatment method.
A number of surface treatment techniques for polymeric materials are known in the art: Corona Discharge, Flame Treatment, Acid Etching, and a number of other methods intended to perform chemical modification of the surface. Among the disadvantages of these techniques are the use of or production of hazardous chemicals, the often excessive depth of treatment, non-uniformity of treatment at a microscopic level, and often severe etching and pitting that leads to changes in surface topography. The depth of treatment is important because with clear materials such as those required for lenses the optical clarity and surface smoothness become affected after an excessively harsh treatment.
Treatment of polymeric surfaces by gas plasmas provides the advantages of very low treatment depth, and uniformity on a microscopic scale. A gas plasma (also known as glow discharge) is produced by electrical discharge in a gas atmosphere at reduced pressure (“vacuum”). It creates a stable, partially ionized gas that may be utilized for effecting reactions on the surface of the substrate because the gas plasma environment activates even chemical compounds that are unreactive under normal conditions. The treatment intensity at the surface is generally relatively strong, and yet the penetration depth of gas plasma treatment is very low, of the order of 5 to 50 nanometres, at a treatment intensity sufficient for useful surface modification. Surface topography and optical clarity do not change unless exposure to the plasma is performed for periods of time much exceeding the time required for achieving the desired chemical modification of the surface. There occurs, therefore, significantly less alteration of the properties of the bulk material than with alternative treatment technologies.
Gas plasma techniques can have two classes of outcomes. In the first, commonly called plasma surface treatment, the surface of a polymeric material to be treated (“the substrate”) is subjected to a plasma established in one or more inorganic vapors or some select organic vapors, and the plasma treatment causes the replacement of some of the original chemical groups on a polymer surface by other, novel groups which are contributed from the plasma gas. For instance, the plasma surface treatment of polytetrafluoroethylene in an ammonia plasma leads to the abstraction of some of the surface fluorine atoms by C—F bond breakage and the incorporation into the modified surface layer of amine groups by C—N bond formation. Plasma surface treatment in an appropriate vapor such as ammonia, carbon dioxide, or water vapor, can therefore be used to place on the surface of any polymeric material reactive chemical groups, such as amine, carboxyl, or hydroxyl, suitable for the subsequent covalent immobilization of various molecules.
The second type of plasma technique is commonly called plasma polymerization and occurs when a discharge is struck in most organic vapors. In contrast to plasma surface treatment, in which less than a monolayer of new material is added, the technique of plasma polymerization leads to the formation of film coatings which can be several micrometers thick and can completely mask the substrate.
Plasma polymers are also covalently bonded to the underlying substrate. The covalent attachment of the plasma coating to the bulk material ensures that the plasma polymer does not detach. Furthermore, plasma polymers are highly crosslinked and do not possess low molecular weight fragments which might migrate into body tissue or fluids.
By appropriate choice of the monomer vapor and the plasma conditions, plasma polymer coatings can be fabricated to contain specific, chemically reactive groups which are also suitable for the subsequent chemical attachment of various molecules to the surface. In the present invention, the surface of a polymeric material which does not inherently carry suitable reactive groups can be activated by plasma surface treatment, plasma polymerization, or plasma polymerization followed by a subsequent plasma surface treatment.